title: Epstein-Barr virus-mediated transformation of B cells induces global chromatin changes independent to the acquisition of proliferation.
abstract: Epstein-Barr virus (EBV) infects and transforms human primary B cells inducing indefinite proliferation. To investigate the potential participation of chromatin mechanisms during the EBV-mediated transformation of resting B cells we performed an analysis of global changes in histone modifications. We observed a remarkable decrease and redistribution of heterochromatin marks including H4K20me3, H3K27me3 and H3K9me3. Loss of H4K20me3 and H3K9me3 occurred at constitutive heterochromatin repeats. For H3K27me3 and H3K9me3, comparison of ChIP-seq data revealed a decrease in these marks in thousands of genes, including clusters of HOX and ZNF genes, respectively. Moreover, DNase-seq data comparison between resting and EBV-transformed B cells revealed increased endonuclease accessibility in thousands of genomic sites. We observed that both loss of H3K27me3 and increased accessibility are associated with transcriptional activation. These changes only occurred in B cells transformed with EBV and not in those stimulated to proliferate with CD40L/IL-4, despite their similarities in the cell pathways involved and proliferation rates. In fact, B cells infected with EBNA-2 deficient EBV, which have much lower proliferation rates, displayed similar decreases for heterochromatic histone marks. Our study describes a novel phenomenon related to transformation of B cells, and highlights its independence of the pure acquisition of proliferation.
authors.affiliation: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Avda. Gran Via 199-203, 08908 L'Hospitalet de Llobregat, Barcelona, Spain, Department of Experimental and Health Sciences, Barcelona Biomedical Research Park, Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain, Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka 1000, Bangladesh, Center for Integrated Protein Science and Adolf-Butenandt Institute, Ludwig Maximilians University of Munich, 80336 Munich, Germany and CR-UK Institute for Cancer Studies, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Henar
authors.initials: H
authors.lastname: Hernando
authors.forename: Abul B M M K
authors.initials: AB
authors.lastname: Islam
authors.forename: Javier
authors.initials: J
authors.lastname: Rodríguez-Ubreva
authors.forename: Ignasi
authors.initials: I
authors.lastname: Forné
authors.forename: Laura
authors.initials: L
authors.lastname: Ciudad
authors.forename: Axel
authors.initials: A
authors.lastname: Imhof
authors.forename: Claire
authors.initials: C
authors.lastname: Shannon-Lowe
authors.forename: Esteban
authors.initials: E
authors.lastname: Ballestar
mesh_terms: D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D049109:Cell Proliferation; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006570:Heterochromatin / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D014170:Transformation, Genetic
chemical_list: D006570:Heterochromatin; D006657:Histones